Monomers with urea groups

ABSTRACT

There is disclosed a family of new vinyl monomers capable of forming polymers by free radical polymerization. The vinyl monomer is of the formula ##STR1## wherein R 1  and R 2  are substituted or unsubstituted hydrocarbons, X is O, NH or NR 3 , and R 3  is substituted or unsubstituted hydrocarbon. 
     The intermediates in the synthesis of these monomers are new beta-chloroalanine ureas. The polymers are useful in film and fiber formation and display good toughness. These new vinyl monomers also form a cyclic monomer.

BACKGROUND OF THE INVENTION

Alpha-aminopropenoic acid derivatives having low molecular weightsubstituents attached to the carbonyl group are known; see for exampleU.K. Patent Specification No. 1,354,571 and U.S. Pat. No. 4,613,658.These compounds are useful as biochemical antibiotic precursors,synthetic nucleic acid mimics, cross-linking agents, monolayers,vesicles, and liquid crystalline solids. The melting point and glasstransition point of many of these compounds, however, is low. The lowmelting point and low glass transition point reduces the utility ofthese compounds in many applications.

SUMMARY OF THE INVENTION

The present invention is directed to new vinyl monomers containingsubstituted urea pendant groups, the polymers resulting therefrom, andthe beta-chloroalanine intermediates of the monomer synthesis. Moreparticularly, the invention is directed to vinyl monomers(alpha-aminopropenoic acid derivatives) of the formula ##STR2## whereinR₁ and R₂ are substituted or unsubstituted hydrocarbons, X is O, NH, orNR₃, and R₃ is a substituted or unsubstituted, hydrocarbon. Theinvention is also directed to the corresponding beta-chloroalaninederivatives which are precursors to the monomers. Polymers can be madefrom the linear and cyclic monomers using, for example, normal freeradical conditions.

The polymers of the present invention have uses such as (i)biocompatible and/or biodegradable encapsulation for controlled drugrelease, (ii) functional vesicles for antibody or antigen specificdiagnostic tests, (iii) in vivo/in vitro studies of the mechanism(s) ofendocytosis, (iv) impact modifiers of commercial polymers, i.e., apolymeric plasticizer, and (v) monolayer and Langmuir/Blodgettfilm-formers which can be subsequently polymerized and used for surfacemodification and coatings applications. The polymers of the presentinvention are new thermoplastic or thermoset polymers having a highmelting point, high glass transition point, and good toughness. Theseproperties make the polymers resistant to a wider range of temperaturesand solvents than the polymers in the aforementioned U.K. Patent No.1,354,571 and U.S. Pat. No. 4,613,658. The polymers can be used for bothfilms and fiber formation.

Due to the presence of the R₁ NH-- group, the compounds of thisinvention exhibit increased hydrogen bonding over the prior artcompounds. This increased hydrogen bonding leads to higher meltingpoints and glass transition points, thereby making the compounds usefulfor a wider range of applications than the prior art compounds.

DETAILED DESCRIPTION OF THE INVENTION

Alpha-aminopropenoic acid derivatives and their beta-chloroalanineprecursors of the present invention are characterized by the presence ofan R₁ NH group adjacent to the carbonyl moiety. The R₁ group can be anysubstituted or unsubstituted hydrocarbon. Preferably, R₁ is selectedfrom the group consisting of substituted and unsubstituted short chainand long chain alkyls, substituted and unsubstituted aryls, andsubstituted and unsubstituted short chain and long chain aralkyls. Inexperiments to date, favorable results have been achieved when R₁ isselected from the group consisting of C₁ -C₂₀ alkyls, C₁ -C₂₀ aralkyls,C₁ -C₂₀ aralkylsulfonyls, and nitroaryls. Representative R₁ groups aremethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclohexyl,octadecyl, diisohexyl, phenyl, otolyl, m-tolyl, p-tolyl,p-toluenesulfonyl, 4-nitrophenyl, R-(+)-methylbenzyl, andS-(-)-methylbenzyl and isomers thereof.

The R₂ group can be any substituted or unsubsituted hydrocarbon.Representative R₂ groups are methyl and short chain alkyls. The X groupcan be O, NH or NR₃. R₃ can be any substituted or unsubstitutedhydrocarbon.

One method for the production of the alpha-aminopropenoic acidderivatives of the present invention is a multi-step procedure startingfrom commercially available D,L-serine wherein the serine is treated toform the hydrochloride salt (optionally esterified or converted to amidederivatives) which is reacted with phosphorous pentachloride (PCl₅) toform 3-chloroalanine hydrochloride salt. The 3-chloroalaninehydrochloride salt is reacted with an isocyanate (R₁ --N═C═O) to form a3-chloroalanine derivative of the formula ##STR3## wherein R₁, R₂ and Xare as previously defined. Any isocyanate can be used in this reaction.Given the high reactivity of the isocyanate moiety, all isocyanates willreact with 3-chloroalanine via the same reaction mechanism. Thus, R₁ canbe any substituted or unsubstituted hydrocarbon group. The3-chloroalanine derivative is isolated and purified byrecrystallization, or is reacted with base to form the dehydroalaninederivative comparable to the formula of the alpha-aminopropenoic acidderivatives of the present invention.

The phenyl, o-tolyl, p-tolyl, 4-nitrobenzyl, and methyl dehydroalaninederivatives, and isomers thereof, upon addition of one equivalent oftriethylamine base or less, form a cyclic product of the formula##STR4##

In addition to the methods disclosed supra for the production ofalpha-aminopropenoic acid derivatives of the present invention, othersynthetic routes are available for the production thereof including thetreatment of alanine and cysteine. Other techniques includebeta-elimination reactions of (i) O-mesylate or O-tosylate derivativesof serine, (ii) sulfinium or sulfinyl derivatives of cysteine, (iii)cysteine reacted with silver carbonate, and (iv) N-chloro derivatives ofalanine. Also available are (v) the Hofmann degradation ofdiaminopropionyl residues, (vi) the rhenium sulfide catalyzed reactionof anhydrides with methyl-2-azidopropionate, and (vii) directdehydration of serine residues with triphenylphosphine and diethylazodicarboxylate or N,N'-disubstituted carbodiimides and cuprouschloride catalyst.

The new monomers of the present invention can be polymerized using freeradical techniques and other methods known in the art. The resultingpolymer has a structure as follows ##STR5## wherein R₁, R₂ and X are aspreviously defined and n is an integer greater than or equal to 2. Theresulting product has a molecular weight of up to about 15,000,000 andpreferably from about 10,000 to about 2,500,000 as estimated bycapillary viscometry.

These polymers have been found to be soluble in a variety of organicsolvents including acetone, chloroform, 1,4-dioxane, ethyl acetate,methylene chloride, and tetrahydrofuran. The methyl and ethyl derivativepolymers are also soluble in water.

The molecular weights of the polymers prepared by the free radicalpolymerization of the alpha-aminopropenoic acid derivatives of thepresent invention range from 10,000 to 2,500,000 daltons as estimated bycapillary viscometry. Various peroxides and azo initiators can be usedin the free radical polymerization. Representative compounds includepotassium peroxydisulfate [K₂ S₂ O₈ ], 2,2'-azobis-(isobutyronitrile)[AIBN], and 2,2'-azobis-(2-amidinopropane) hydrochloride [V-50].Photoinitiators such as V-50, 2,2-dimethoxy-2-phenyl acetophenone[Irgacure 651], diethoxy acetophenone [DEAP], and benzophenone can alsobe used.

Bulk or solution polymerization of the monomer usually takes placewithin four hours at temperatures from room temperature to 100° C. atatmospheric pressure. The methyl, ethyl, R-(+)-methylbenzyl. andS-(-)-methylbenzyl derivatives and isomers thereof spontaneouslypolymerized at temperatures greater than 60° C. under reduced pressure.Photopolymerization of monomer films takes place after five or lesshours of irradiation.

The following examples are representative of the invention.

EXAMPLE 1

Monomer synthesis is accomplished by the methyl esterification,beta-chlorination, and dehydrochlorination of D,L-serine to formdehydroalanine derivatives.

Commercial D,L-serine is reacted with excess HC1 saturated methanol at40° C. for four hours. The solvent is removed under reduced pressure andvacuum oven drying; the D,L-serine methyl ester hydrochloride salt isadded in small portions over a period of two hours to a stirredsuspension of 10% molar excess phosphorous pentachloride in2-nitropropane at 10° C. The mixture is kept at 10° C. overnight tocomplete the reaction. The suspension is filtered and the whitecrystalline product [3-chloroalanine methyl ester hydrochloride salt] isrinsed with methylene chloride and anhydrous acetone. The3-chloroalanine methyl ester hydrochloride salt is added to excess ethylacetate and stirred at 10° C. One molar equivalent of triethylamine baseis added and the mixture is stirred for one hour. One molar equivalentof an isocyanate is added portion wise to the stirred suspension over aperiod of one hour at 10° C. The mixture is allowed to come to roomtemperature and is stirred overnight to ensure complete reaction. Thinlayer chromatography (ethyl acetate solvent) is used to determine whenthe reaction was complete. The suspension is filtered to remove thetriethylamine hydrochloride salt and the filtrate is washed twice with0.1N HC1 and once with an equal volume of deionized water. Solventremoval under reduced pressure and moderate temperature to remove mostof the solvent results in a clear oil product with precipitated theN-(N'-alkylcarbamoyl)-3-chloroalanine methyl ester upon cooling to 10°C. Repeated reprecipitation in ethyl acetate results in a clean productas determined by gas chromatography and ¹³ C NMR. The purified3-chloroalanine product is dissolved in excess ethyl acetate held at 10°C. with vigorous stirring. One equivalent of triethylamine base is addedportionwise over a period of one hour and the mixture was brought up to40° C. for two hours to complete the dehydrohalogenation reaction. Thereaction mixture is stored overnight in a refrigerator. Thin layerchromatography (ethyl acetate solvent) is used to determine when thereaction is complete. The mixture is filtered to remove thetriethylamine hydrochloride salt and the filtrate is washed twice with0.1N HC1 and once with an equal volume of deionized water. Solventremoval under reduced pressure and moderate temperature results in aclear oil product which is the N-(N'-alkylcarbamoyl)-dehydroalaninemethyl ester. This method affords a clean product which can be easilypurified by repeated cold crystallizations from ethyl acetate.

Alternatively, the intermediate beta-chloroalanine urea is not isolatedand purified, but is treated directly in the crude reaction mixture withone additional equivalent of triethylamine to give theN-(N'-alkylcarbamoyl)-dehydroalanine methyl ester. Purification is thenthe same as above involving extractions and recrystallizations.

Using the method described above, methyl isocyanate [CH₃ N═C═O] is usedto obtain N-(N'-methylcarbamoyl)dehydroalanine methyl ester as a clearyellow oil which spontaneously polymerizes upon removal of the solventat 40° C. under vacuum. Alternatively, addition of one mole equivalentof triethylamine base at room temperature before solvent removal causesthe dehydroalanine derivative to form a cyclic derivative by loss of theester alcohol group after twenty four hours.

EXAMPLE 2

Using the method described in Example 1, ethyl isocyanate [CH₃ CH₂N═C═O] is used to obtain the crystalline beta-chloroalanine compound andthe N-(N'ethylcarbamoyl)dehydroalanine methyl ester as a clear yellowoil which spontaneously polymerizes upon removal of the solvent at 40°C. under vacuum.

EXAMPLE 3

Using a method described in Example 1, propyl isocyanate [CH₃ (CH₂)₂N═C═O] is used to obtain the crystalline betachloroalanine compound andthe N-(N'-propylcarbamoyl)dehydroalanine methyl ester as a clear yellowoil which is purified by crystallization in ethyl acetate at 10° C.

EXAMPLE 4

Using the method described in Example 1, isopropyl isocyanate [(CH₃)₂CHN═C═O] is used to obtain the crystalline beta-chloroalanine compoundand N-(N'-isopropylcarbamoyl)dehydroalanine methyl ester as a clearyellow oil which is purified by crystallization in ethyl acetate at 10°C.

EXAMPLE 5

Using the method described in Example 1, butyl isocyanate [CH₃ (CH₂)₃N═C═O] is used to obtain the crystalline betachloroalanine compound andN-(N'-butylcarbamoyl)-dehydroalanine methyl ester as a clear yellow oilwhich is purified by crystallization in ethyl acetate at 10° C.

EXAMPLE 6

Using the method described in Example 1, tert.butyl isocyanate [(CH₃)₃CN═C═O] is used to obtain the crystalline beta-chloroalanine compoundand N-(N'-tert-butylcarbamoyl)dehydroalanine methyl ester as a clearyellow oil which is purified by crystallization in ethyl acetate at 10°C.

EXAMPLE 7

Using the method described Example 1, cyclohexyl isocyanate [(CH₂)₅CHN═C═O] is used to obtain the crystalline beta-chloroalanine compoundand N-(N'-cyolohexyloarbamoyl)dehydroalanine methyl ester as a clearyellow oil which is purified by crystallization in ethyl acetate at 10°C.

EXAMPLE 8

Using the method described in Example 1, octadecyl isocyanate [CH₃(CH₂)₁₇ N═C═O] is used to obtain the crystalline beta-chloroalaninecompound and N-(N'-octadecylcarbamoyl)dehydroalanine methyl ester as aclear yellow oil which is purified by crystallization in isomerichexanes at -40° C. Due to the limited solubility of the 3-chloroalaninederivative, the dehydrohalogenation reaction is carried out at 60° C. intetrahydrofuran with vigorous stirring. This results initially in aslurry which becomes a clear solution as the reaction proceeds.

EXAMPLE 9

Using the method described in Example 1, 1,6-hexanediisocyanate[O═C═N(CH₂)₆ N═C═O] is used to obtain1,6-bis[N-(N'-diisohexylcarbamoyl)dehydroalanine methyl ester]. Theinsolubility of the 3-chloroalanine derivative requiresdehydrohalogenation reaction conditions as in Example 8.

EXAMPLE 10

Using the method described in Example 1, R-(+)-methylbenzyl isocyanate[C₆ H₅ --CHCH₃ --N═C═O] is used to obtain the crystallinebeta-chloroalanine compound andN-(N'-R-(+)-methylbenzylcarbamoyl)-dehydroalanine methyl ester as aclear yellow oil which spontaneously polymerizes upon removal of thesolvent at 40° C. under vacuum.

EXAMPLE 11

Using the method described in Example 1, S-(-)-methylbenzyl isocyanate[C₆ H₅ --CHCH₃ --N═C═O] is used to obtain the crystallinebeta-chloroalanine compound andN-(N'-S-(-)-methylbenzylcarbamoyl)-dehydroalanine methyl ester as aclear yellow oil which spontaneously polymerizes upon removal of thesolvent at 40° C. under vacuum.

EXAMPLE 12

Using the method described in Example 1, p-toluenesulfonyl isocyanate[CH₃ --C₆ H₄ --SO₂ --N═C═O] is used to obtain the crystallinebeta-chloroalanine compound andN-(N'-p-toluenesulfonylcarbamoyl)-dehydroalanine methyl ester as a clearyellow oil which is purified by crystallization in ethyl acetate at 40°C.

EXAMPLE 13

Using the method described in Example 1, phenyl isocyanate [C₆ H₅--N═C═O] is used to obtain the crystalline beta-chloroalanine compoundand N-(N'-phenylcarbamoyl)-dehydroalanine methyl ester as a clear yellowoil which is purified by crystallization in ethyl acetate at 40° C. Thedehydrohalogenation reaction is carried out at 10° C. Upon addition ofone mole equivalent of triethylamine base at room temperature, thedehydroalanine derivative forms the cyclic compound. This product isseparated by column chromatography and purified by crystallization inethyl acetate.

EXAMPLE 14

Using the methods described in Examples 1 and 13, o-tolyl isocyanate[CH₃ --C₆ H₅ --N═C═O] is used to obtain the crystallinebeta-chloroalanine compound, N-(N'-o-tolylcarbamoyl)dehydroalaninemethyl ester and the cyclic derivative which are purified bycrystallization in ethyl acetate at 40° C.

EXAMPLE 15

Using the methods described in Examples 1 and 13, m-tolyl isocyanate[CH₃ --C₆ H₅ --N═C═O] is used to obtain the crystalline dehydroalaninemethyl ester and the cyclic derivative which are purified bycrystallization in ethyl acetate at 40° C.

EXAMPLE 16

Using the methods described in Examples 1 and 13, p-tolyl isocyanate[CH₃ --C₆ H₅ --N═C═O] is used to obtain the crystallinebeta-chloroalanine compound, N-(N'-p-tolylcarbamoyl)dehydroalaninemethyl ester and the cyclic derivative which are purified bycrystallization in ethyl acetate at 40° C.

EXAMPLE 17

Using the methods described in Examples 1 and 13, 4-nitrophenylisocyanate [NO₂ --C₆ H₅ --N═C═O] is used to obtain the crystallinebeta-chloroalanine compound,N-(N'-4-nitrophenylcarbamoyl)-dehydroalanine methyl ester and the cyclicderivative which are purified by crystallization in ethyl acetate at 40°C.

EXAMPLE 18

Free radical polymerizations are performed in benzene using Vazo 67initiator at 60° C. One gram of monomer is dissolved in benzenecontaining 100 mg Vazo 67. Dry nitrogen is passed through the mixturecontained in a septum capped test tube for five minutes. Thepolymerization tube is then placed into a constant temperature waterbath maintained at 60° C. for at least four hours and up to 24 hours.Solvent removal results in a clear polymer which is dissolved intetrahydrofuran and reprecipitated into ice cold methanol. The polymeris vacuum oven dried to remove traces of solvent.

Using the method described above, N-(N'-propylcarbamoyl)dehydroalaninemethyl ester is polymerized, giving a polymer with an intrinsicviscosity of 0.20 dL/g.

EXAMPLE 19

Using the method described in example 18,N-(N'-isopropylcarbamoyl)-dehydroalanine methyl ester is polymerized,giving a polymer with an intrinsic viscosity of 0.54 dL/g.

EXAMPLE 20

Using the method described in Example 18,N-(N'-butylcarbamoyl)-dehydroalanine methyl ester is polymerized, givinga polymer with an intrinsic viscosity of 0.54 dL/g.

EXAMPLE 21

Using the method described in Example 18.N-(N'-tert.Butylcarbamoyl)-dehydroalanine methyl ester is polymerized.

EXAMPLE 22

Using the method described in Example 18,N-(N'-cyclohexylcarbamoyl)-dehydroalanine methyl ester is polymerized,giving a polymer with an intrinsic viscosity of 0.10 dL/g.

EXAMPLE 23

Using the method described in Example 18,N-(N'-diisohexylcarbamoyl)-bis-dehydroalanine methyl ester ispolymerized. The product is insoluble in organic solvents.

EXAMPLE 24

Using the method described in Example 18,N-(N'-octadecylcarbamoyl)-dehydroalanine methyl ester is polymerized.

EXAMPLE 25

Using the method described in Example 18,N-(N'-phenylcarbamoyl)-dehydroalanine methyl ester is polymerized.

EXAMPLE 26

Using the method described in Example 18,N-(N'-o-tolylcarbamoyl)-dehydroalanine methyl ester is polymerized.

EXAMPLE 27

Using the method described in Example 18,N-(N'-tolycarbamoyl)-dehydroalanine methyl ester is polymerized.

EXAMPLE 28

Using the method described in Example 18,N-(N'-p-tolylcarbamoyl)-dehydroalanine methyl ester is polymerized.

EXAMPLE 29

Using the method described in Example 18,N-(N'-p-tolueneslfonylcarbamoyl)-dehydroalanine methyl ester ispolymerized.

EXAMPLE 30

At 40° C. under reduced pressure, N-(N'-methylcarbamoyl)dehydroalaninemethyl ester spontaneously polymerizes, giving a polymer with anintrinsic viscosity of 0.40 dL/g.

EXAMPLE 31

At 40° C. under reduced pressure, N-(N'-ethylcarbamoyl)dehydroalaninemethyl ester spontaneously polymerizes, giving a polymer with anintrinsic viscosity of 0.22 dL/g.

EXAMPLE 32

At 40° C. under reduced pressure,N-(N'-R-(+)-methylbenzylcarbamoyl)-dehydroalanine methyl esterspontaneously polymerizes.

EXAMPLE 33

At 40° C. under reduced pressure,N-(N'-S-(-)-methylbenzylcarbamoyl)-dehydroalanine methyl esterspontaneously polymerizes.

EXAMPLE 34

The procedure of Example 1 is repeated, with the exception that excessHC1 saturated propanol is substituted for the excess HC1 saturatedmethanol. The resultant monomer is N-(N'-methylcarbamoyl)-dehydroalaninepropyl ester.

EXAMPLE 35

The procedure of Example 1 is repeated, with the exception that excessHCl saturated hexanol is substituted for the excess HCl saturatedmethanol. The resultant monomer is N-(N'-methylcarbamoyl)-dehydroalaninehexyl ester.

EXAMPLE 36

The procedure of Example 1 is repeated, with the exception that theamide derivative of D,L-serine, CH₂ OH.CHNH₂.CONH₂, is substituted forserine. The resultant monomer is N-(N'-methylcarbamoyl)-dehydroalaninemethyl amide, CH₃ NHCO.NHCCH₂ CONHCH₃.

EXAMPLE 37

The procedure of Example 1 is repeated, with the exception that themethyl amide derivative of D,L-serine, CH₂ OH.CHNH₂.CONHCH₃ issubstituted for serine. The resultant monomer isN-(N'-methylcarbamoyl)-dehydroalanine dimethyl amide, CH₃ NHCO.NHCCH₂CON(CH₃)₂.

EXAMPLE 38

The procedure of Example 1 is repeated, with the exception that theoctylamide derivative of D,L-serine, CH₂ OH.CHNH₂.CONHC₈ H₁₉ issubstituted for serine. The resultant monomer isN-(N'-methylcarbamoyl)-dehydroalanine methyloctyl amide, CH₃ NHCO.NHCCH₂CONCH₃ C₈ H₁₉.

What is claimed is:
 1. A compound of the formula ##STR6## wherein R₁ isselected from the group consisting of C₁ -C₂₀ alkyls, C₁ -C₂₀ aralkyls,C₁ -C₂₀ aralkylsulfonyls, arylsulfonyls, unsubstituted aryls, and arylssubstituted with methyl and nitro, R₂ is selected from the groupconsisting of C₁ -C₂₀ alkyls, X is O, NH, or NR₃, and R₃ is selectedfrom the group consisting of short chain alkyls.
 2. The compound ofclaim 1 wherein X is O and R₂ is a short chain alkyl.
 3. The compound ofclaim 2 wherein R₁ is selected from the group consisting of C₁ -C₂₀alkyls.
 4. The compound of claim 2 wherein R₁ is selected from the groupconsisting of C₁ -C₂₀ aralkyls.
 5. The compound of claim 2 wherein R₁ isselected from the group consisting of C₁ -C₂₀ aralkylsulfonyls.
 6. Thecompound of claim 2 wherein R₁ is selected from the group consisting ofnitroaryls.
 7. The compound of claim 1 wherein X is O, R₂ is CH₃ and R₁is selected from the group consisting of methyl, ethyl, propyl, butyl,cyclohexyl, octadecyl, diso hexyl, methylbenyl, toluenesulfonyl, phenyl,tolyl, nitrobenzyl, and isomers thereof.
 8. A compound of the formula##STR7## wherein R₁, R₂ and X are as defined in claim
 1. 9. The compoundof claim 8 wherein X is O and R₂ is a short chain alkyl.
 10. Thecompound of claim 9 wherein R₁ is selected from the group consisting ofC₁ -C₂₀ alkyls.
 11. The compound of claim 9 wherein R₁ is selected fromthe group consisting of C₁ -C₂₀ aralkyls.
 12. The compound of claim 9wherein R₁ is selected from the group consisting of C₁ -C₂₀aralkylsulfonyls.
 13. The compound of claim 9 wherein R₁ is selectedfrom the group consisting of nitroaryls.
 14. The compound of claim 8wherein X is O, R₂ is CH₃ and R₁ is selected from the groups consistingof methyl, ethyl, propyl, butyl, cyclohexyl, octadecyl, diiso hexyl,methylbenzyl, toluenesulfonyl, phenyl, tolyl, nitrobenzyl, and isomersthereof.
 15. The compound of claim 1, wherein R₃ is methyl.
 16. Thecompound of claim 8, wherein R₃ is methyl.